More than 18 million Americans suffer today from insulin-dependent, type II diabetes. It is estimated that half of type II diabetics are unable or unwilling to properly gluco-regulate themselves using the standard finger stick regimen. Many of these people would benefit greatly from an indwelling, closed loop insulin delivery device, e.g. the artificial pancreas that employs a sensor to continuously monitor glucose levels in either blood or interstitial fluid. Although several groups have reported biosensors that have successfully functioned for weeks to months in vivo, no glucose sensor appears capable of reliably and predictably surviving long-term implantation. Consequently, all FDA-approved glucose sensors are deemed suitable for acute applications only. Hypothesis: Our global hypothesis is that the last remaining barrier to the application long-term indwelling of glucose sensors is surviving wound-healing mediated sensor failure. We address this hypothesis by devising and characterizing membrane modifications and local release strategies that (1) resist biofouling, (2) attenuate inflammation, (3) reduce the fibrosity and (4) promote vascularity of the surrounding wound healing tissue will minimize impediments to glucose transport across the sensor membrane. This competitive renewal is divided into translational and experimental objectives. The translational objective is the application of dexamethasone, VEGF and texturing strategies developed in the previous funding cycle to FDA-approved Medtronic Diabetes SOF-SENSORTM glucose sensors. This will include implantation in intact tissue, as well as the first-time use of a dorsal transcutaneous window chamber rat model to directly observe the evolution of tissue architecture in the vicinity immediately adjacent to a subcutaneously implanted sensor. The experimental objectives also examine biomimetic strategies that employ seeded adipose-derived stems cells (ASC) for mediating inflammation and promoting vessel formation in the tissue surrounding implanted sensors. In each case, the experimental results from the window chamber images and the live senor responses will be benchmarked using transport modeling of perfusion of the sensor surface with blood borne glucose. A more precise model will be used to predict the anticipated affects of microvessel density, fibrous encapsulation, and biofouling on the observed sensor response. PUBLIC HEALTH RELEVANCE: This project addresses the last remaining barrier to the application long-term indwelling of glucose sensors - the inability of sensors to reliably and predictably survive long- term implantation.